Characterization for Novel Biotherapeutics

- 新生物治疗的表征分析 -


As new product formats progress through development and into the regulatory process, the role of analytical characterization is taking on new meaning. Very new modalities present challenges to both analytical scientists and regulatory agencies alike, and this steep learning curve requires a near-constant cycle of adaptation and innovation. The PEGS Characterization of Biotherapeutics conference explores the progression of analytical development for an exciting range of emerging modalities and offers a case study forum for those working in the field to share ideas, experiences and solutions that support the preclinical and clinical development of novel biotherapeutics.

Final Agenda

5月3日(日)

Recommended Short Course(s)*

SC2: Translational Biotherapeutic Development Strategies: Part I, Discovery, Molecular Assessment and Early Stage Development

SC6: Translational Biotherapeutic Development Strategies: Part II, Analytical and Clinical Considerations

*Separate registration required.

5月4日(一)

7:00 am Registration and Morning Coffee

ANTIBODY-DRUG CONJUGATES

8:30 Chairperson’s Opening Remarks

Cexiong (Winston) Fu, PhD, Principal Scientist, Takeda

8:40 Analytical Toolbox for Measuring the Drug-Antibody Ratio of Antibody Drug Conjugates

Delphine Mathieu, PhD, Head, ADC Analytical Skill Center, Biologics Development Sanofi, France

Drug-Antibody Ratio (DAR) is a critical quality attribute for antibody-drug conjugates. Depending on conjugation technology (lysine or cysteine residues, stochastic or site specific) and nature of the drug, DAR is determined thanks to a complete panel of analytical methods, from spectrophotometry to hydrophobic chromatography or drug distribution profile. Beyond DAR, conjugation sites are characterized through a set of MS-based analytical methods enabling in-depth product understanding.

9:10 Next Wave of ADC Characterization, from Top to Down

Cexiong (Winston) Fu, PhD, Principal Scientist, Takeda

Top-down analysis plays increasingly key roles in the characterization of biologics. We will demonstrate examples of novel top-down online LC-MS application for ADC analysis to elucidate multiple critical quality attributes, including DAR determination, DAR species distribution, positional isomers profiling, conjugation site, and occupancy analysis. Lastly, an ELISA-based protein conformational assay with high sensitivity will discover subtle local conformational alteration of ADC and correlate to the occupancy rate of drug conjugation.

9:40 Application of Charge-Based Separation Techniques to Expand the Analytical Toolkit for Charged ADC Molecules

Sunnie Kim, PhD, Senior Scientist, Seattle Genetics

The physicochemical properties of ADCs can be highly dependent on the chemical nature of the drug linker (DL) and can impact the selection of an appropriate analytical technique for ADC testing. Here, case studies on the application of charge separation, icIEF and IEX, to enhance the capability of release methods to monitor additional DL-related attributes will be presented. These allow for maximizing our analytical toolkit and increasing efficiency.

10:10 Networking Coffee Break

TRANSITIONING FROM THERAPEUTIC PROTEINS TO CELL AND GENE THERAPIES

10:50 The Experience of a Protein Biochemist Transitioning to Gene Therapy

George Bou-Assaf, PhD, Scientist, Analytical Development – Product & Technology Development, Biogen

Gene therapy products comprise a protein capsid and a nucleic acid packaged inside. We describe how analytical tools traditionally employed by biochemists for protein therapeutics are applied as is, or are adapted to gene therapy products. We highlight similarities between gene therapy and protein-based products and discuss specific examples related to their critical quality attributes. We describe challenges unique to gene therapy products and how they were overcome with new methods.

11:20 Key Assays and Methods for Generation, In-Process Testing and Characterization, towards CMC of AAV Vectors

Stefan Seeber, PhD, Senior Principal Scientist, Cell Technologies, Roche Pharma Research and Early Development, Germany

As AAV-based gene therapy is coming of age with clinical success and increasing numbers of market entries, the pharma industry has set out to develop AAV vector production protocols according to CMC standards. We are leveraging our expertise in CMC for therapeutic proteins to adopt existing and integrate new protocols for AAV vector generation, purification, and quality control. A case study will be presented to illustrate the challenges related to differences between therapeutic modalities.

11:50 KEYNOTE PRESENTATION: Expanding Analytical Capabilities from Protein Biologics to Gene Therapy Products

Julia Ding, PhD, Director, Process Analytics & Analytical Development, Bristol-Myers Squibb

With the advance of modern analytical technologies, protein biologics are well characterized at the molecular level. Product critical quality attributes are assessed through a structure-functional relationship and controlled throughout process and product development. Analytical paradigm of gene therapy products has brought significant challenges in analytical standardization and control strategy. Case studies in adapting and advancing analytical capability in support of viral vector development will be presented.

12:20 pm Fast, Low Volume Subvisible Particle Analysis with HORIZON

Renee Tobias, Director, Marketing, HALO LABS

The HORIZON is the industry's first analytical system to address the need for rapid, comprehensive subvisible particle analysis even when limited sample material is available. Based on the USP <788> method of Membrane Microscopy, image analysis on HORIZON is fully automated, uses a simple 96-well plate based approach, and required only 25µL per sample. HORIZON enables incorporation of subvisible particle analysis into biologics workflows as early developability assessment through late stage formulation and QC.

12:50 Session Break

12:55 Luncheon Presentation I to be Announced

1:25 Luncheon Presentation II (Sponsorship Opportunity Available)

1:55 Session Break

2:20 Problem-Solving Breakout Discussions - View All Breakout Discussion Topics

TABLE: Co-formulation of Therapeutic Proteins

Moderator: Dennis Krieg, PhD, Researcher, Pharmaceutical Technology & Biopharmaceutics, Ludwig-Maximilians-University Munich, Germany

  • Analytical challenges (deconvolution of chromatographic and spectroscopic data, systematic and efficient method development
  • Formulation challenges (DoE approaches, setup of stability studies for co-formulations)
  • Regulatory challenges (demands for co-formulation characterization by the regulatory authorities, use of single formulation stability data for co-formulations)
  • Clinical challenges (setup of PK studies for flexible or fixed dosing ratios, extrapolation of clinical data from single to co-formulations)

TABLE: Challenges Associated with Analytical Method Development for the Characterization of AAV-Based Therapeutics

Moderator: George Bou-Assaf, PhD, Scientist, Analytical Development, Product & Technology Development Biogen

  • Similarities and differences between AAV and protein-based challenges
  • Transferability of methods from proteins to AAV-based molecules
  • Sample limitations and design of experiments to take into account this limitation
  • Simplified and streamlined approaches to method development that still meets ICH guidelines and regulatory expectations
  • New tools and instrumentations that enable analytical method development of AAV based therapeutics

3:20 Networking Refreshment Break

PLENARY KEYNOTE SESSION

4:00 Chairperson’s Remarks

K. Dane Wittrup, PhD, J.R. Mares Professor, Chemical Engineering & Bioengineering, Massachusetts Institute of Technology

4:10 From Energy to Machine Learning

George-ChurchGeorge Church, PhD, Professor of Genetics, Harvard Medical School; Professor of Health Sciences and Technology, Harvard and the Massachusetts Institute of Technology (MIT)

In 1974, I adapted energy optimization methods for use in models of nucleic acids, protein and their interactions, and then for use in crystallographic refinement. In the last days of the second millennium, David Baker's team won the Critical Assessment of Structure Prediction (CASP) by an unbelievable margin. Since then, our labs exchanged 3 PhD students (Dantas, Raman, Lajoie), for Wannier from Mayo's group, Stranges from Kuhlman, and Mandell from Kortemme. We engineered new sensor proteins for metabolic engineering, essential proteins with non-standard amino acids for biocontainment, and polymerase-pore fusions for nanopore sequencing. None of this prepared us for the revolution following Gleb Kuznetsov joining our lab in 2012, joined soon by Surge Biswas, Pierce Ogden, Ethan Alley, and Sam Sinai. Together we abruptly moved to "sequence only" deep machine learning for protein design – ranging from fluorescent proteins to AAV capsids to antibodies. When combined with libraries of millions of designed gene segments from chip-synthesis and rapid testing, each design cycle can take large leaps in sequence space and function space.

4:55 The Case for Intelligent Design in Protein Engineering

spangler-jaimeJamie Spangler, PhD, Assistant Professor, Biomedical Engineering and Chemical & Biomolecular Engineering, Johns Hopkins University

Directed evolution is in its prime, and it is deepening our understanding of biological systems and empowering therapeutic design. Recent breakthroughs in structural biology, computational design, and high-dimensional data analytics afford us the unprecedented opportunity to apply molecular, structural, and computational principles to guide protein engineering, employing a so-called “intelligent design” approach. This talk will highlight how my lab harnesses this interfacial approach to overcome the deficiencies of natural proteins.

5:40 Welcome Reception in the Exhibit Hall with Poster Viewing (Co-Sponsorship Opportunity Available)

7:15 End of Day

5月5日(二)

8:00 am Registration and Morning Coffee

EMERGING MODALITIES

8:25 Chairperson’s Remarks

Wendy Sandoval, Principal Scientist, Genentech

8:30 siRNA-mAb Conjugate Analysis: To Ioinise in Positive or Negative ESI Mode, That Is the Question

Iain Campuzano, Principal Scientist, Discovery Attribute Sciences, Amgen

Antibody-drug conjugates are important classes of molecules currently being used to treat multiple diseases. Advances in small-interfering RNA (siRNA) technology result in numerous RNAi-based therapies being pursued in clinical trials. Herein we present how native nESI-MS, in both positive and negative polarities, is the only bona fide analytical method for accurate intact MW and RAR (RNA-to-antibody ratio) calculation for siRNA-mAb conjugates.

9:00 Characterization of Conditionally Activating Biologics

Wendy Ritacco, Senior Scientist, AbbVie Bioresearch Center

Bispecific conditional dual variable domain immunoglobulins (cDVD-Igs) are targeted and locally activated biologics that offer new prospects for engineering efficacy, while minimizing systemic side effects. We will describe preclinical examples of tissue targeting and activation in in vivo disease models as part of a new generation of locally acting “regio-specific” biologics therapies.

9:30 Analytical Characterization Tools for Rapid Developability Assessment of Recombinant Protein Vaccine Antigens

Kawaljit Kaur, PhD, Associate Researcher, Vaccine Analytics and Formulation Center, Pharmaceutical Chemistry, University of Kansas

Developability data were rapidly generated using only ~1 mg per candidate to assess and compare structural integrity, physical stability (including compatibility with preservatives for multi-dose formulations) and antigenicity of different site-directed mutants of a recombinant rotavirus protein antigen candidate. Correlations of developability data with accelerated stability studies with both liquid and aluminum-adjuvanted formulations helped to inform and optimize formulation design and to rank order pharmaceutical properties of various mutants.

10:00 Coffee Break in the Exhibit Hall with Poster Viewing

DRUG COMBINATIONS

10:50 Release and Stability Testing Challenges for Biotherapeutic Combinations – A Case Study

Ming Zeng, PhD, Associate Director, Parenteral Sciences & Technology Bristol-Myers Squibb

The development of combination biotherapeutics to improve efficacy and address the unmet needs for patients has drawn increased attention in industry. In addition to control each individual drug, the challenge of demonstrating no-impact of the combined drugs requires analytical scientists to think outside the box and come up with an innovative approach in developing an appropriate control strategy for monitoring combination product quality and stability properties. A case study will be presented.

11:20 Use of 2D Liquid Chromatography to Characterize Aggregates in Co-Formulated Drug Products

Xiaoqing Hua, Senior Scientist, Merck

Co-formulated monoclonal antibodies pose new challenges for analytical characterization due to their increased complexity. For example, aggregation is a common degradation pathway for mAbs and is often monitored under native state with size exclusion chromatography (SEC), but for co-formulation, new challenges appear due to similar size and shape of individual mAbs. A 2D-LC approach with orthogonal methods to SEC was adopted to improve product knowledge of single mAb profile in co-formulation and characterize aggregation in co-formulated DPs.

11:50 Overcoming Challenges in Co-Formulation of Therapeutic Proteins with Contradicting Stability Profiles

Dennis Krieg, PhD, Researcher, Pharmaceutical Technology & Biopharmaceutics, Ludwig-Maximilians-University Munich, Germany

In this talk, we present our work on co-formulation of the model proteins, EPO and G-CSF, which are interesting from both clinical and physicochemical perspectives. These cytokines differ a lot in their structure and respective stability profile, so obtaining a stable co-formulation of both proteins in one solution is challenging. We present a systematic approach to study and stabilize these two physicochemical, very different therapeutic proteins in one formulation.

12:20 pm Session Break

12:25 Luncheon Presentation I to be Announced

12:55 LUNCHEON PRESENTATION II: In-Depth Peptide Mapping Profiling of Multispecific Antibodies Using Genedata Expressionist

Soraya Hoelper, PhD, Lab Head Mass Spectrometry, Protein Therapeutics, R&D Biologics Germany, Sanofi-Aventis Deutschland GmbH

Arnd Brandenburg, PhD, Head, Professional Services, Genedata Expressionist, Genedata

1:25 Ice Cream Break in the Exhibit Hall with Poster Viewing and Poster Award

BISPECIFIC AND MULTISPECIFIC ANTIBODIES

2:00 Chairperson’s Remarks

Wendy Ritacco, Senior Scientist, AbbVie Bioresearch Center

2:05 Native Chromatographies to Resolve Mispairs and Determine Optimal Chain Pairing for BsBv Molecules

Wendy Sandoval, Principal Scientist, Genentech

A particular challenge in characterizing impurities resulting from single cell assembly of bispecific antibodies is distinguishing the ‘correct’ molecule from the isobaric light chain-scrambled mispair. Here we present coupled native charge separation-based mass spectrometry platforms, including CV-MS and CZE-MS, to complement current quantitative MS-based approaches. We investigate chromatographic elution order through analytical methods and molecular modeling in an effort to understand the intrinsic charge, size, and shape differences.

2:35 Bispecific Molecules and Characterization for Pharmacokinetics Studies

Mei Han, Senior Scientist, Pharmacokinetics & Drug Metabolism, Amgen

The sophistication required for proper molecular design causes the manufacturing and development of bispecific antibodies to be complex. Monitoring structural stability is critical for retention of the favorable drug distribution and pharmacokinetic of the antibody format. Classic ligand binding assays have limited resolution to capture some structural modifications in bispecifics. Here we will discuss characterization of bispecific molecules from pre-dose and post-dose pharmacokinetic samples.

3:05 Sponsored Presentation (Opportunity Available)

3:35 Refreshment Break in the Exhibit Hall with Poster Viewing

CHARACTERIZATION CHALLENGES

4:25 Factors that Influence Antitumor Activity and Toxicity of Agonist Antibodies

Yoshiko Akamatsu, PhD, Senior Principal Research Scientist, AbbVie

Activities of agonist antibodies are influenced by factors such as hinge flexibility, Fc isotype, and affinity. Importance of these factors varies depending on epitope. We will discuss how to identify and engineer the therapeutic candidates with maximal antitumor activity while minimizing toxicity using TNFSFR agonist antibodies as examples.

4:55 Developability Retrospective: Differentiating between Red Flags and Red Herrings in Developability Assessments

Christina Palmer, Scientist, Antibody Discovery, Biogen

We will present several case studies following the developability assessment of our preclinical to commercial pipeline. These case studies will illustrate how the evolving field of developability can help inform antibody selection and progression through development. We will highlight several examples of red flags and red herrings in developability and shed light on some of the underlying mechanisms and how they relate to antibody development.

5:25 End of Characterization for Novel Biotherapeutics

5:30 Registration for Dinner Short Courses


6:00-8:30 pm Recommended Dinner Short Course*

SC9: Introduction to Biophysical Analysis for Biotherapeutics: Development Applications

*Separate registration required.

* 活动内容有可能不事先告知作更动及调整。

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